About the Project
Gene expression is regulated at multiple layers, from histone modifications (histone code) through RNA processing to protein degradation. Most layers are extensively studied because of their fundamental biological importance and because dysregulation at each layer can lead to diseases. However, the regulatory role of ribosomes (ribosome code) is largely unexplored despite its strong associations with cancer, aging and other diseases.
Notwithstanding decades of research, the evidence that specialized ribosomes can actively regulate gene expression had remained indirect and inconclusive; multiple studies have shown that mutations in core ribosomal proteins (RPs) have highly RP-specific phenotypes in processes including carcinogenesis, aging and cell differentiation. These correlative associations and our observations of differential RP transcription motivated us to directly test whether wildtype cells build specialized ribosomes as a means of controlling protein synthesis. To this end, we developed methods for direct, accurate and precise measurements of protein levels and synthesis rates. These methods allowed us to obtain the first direct evidence for differential stoichiometry among RPs in unperturbed yeast and mammalian stem cells.
This project will substantially expand this methodology and use it to investigate ribosome-mediated translational regulation in differentiating stem cells and in cancer cells. Previous research has indicated that loss of function mutations in some RPs (e.g., RPL5) are associated with poor prognosis of human glioblastomas but the mechanisms of such associations remain unclear. Our preliminary data suggest a conceptual framework for understanding such cases, and more generally a broad framework for active regulation of protein synthesis by specialized ribosomes.
The project will build upon our preliminary data by: (i) employing and expanding our newly-developed methodology for building the first comprehensive map of ribosome modifications, (ii) mapping specific interactions between mRNAs and ribosome modification, (iii) associating these interactions with functional impact on the rates of translation initiation and elongation, and on cell growth, and (iv) testing causal mechanisms suggested by these associations by genetic manipulations of RPs. The proposed methods and experiments have the potential to overcome longstanding roadblocks and to lay the groundwork for understanding ribosome-mediated translational regulation. Such understanding may allow the therapeutic exploitation of the high specificity of RP mutations to particular cancer types.
For more background and highlight of this research project, see http://www.cell.com/trends/biochemical-sciences/abstract/S0968-0004(15)00234-0
I am looking for students who:
-- seek conceptual ideas, enjoy discussing them and testing them rigorously
-- are interested in experimental biology and have or want to develop quantitative skills
-- want to develop and apply algorithms for data analysis, machine
-- learning and statistical inference
-- want to learn (or have experience with) tissue culture and basic
-- molecular biology techniques
-- are creative and enjoy working collaboratively
-- have good communication skills
Students with Masters degrees are strongly encouraged to apply and can receive course credit for their graduate coursework that will count towards the PhD requirements.
For more details on this project, see http://www.northeastern.edu/slavovlab/
To apply for this project, you must also apply to the graduate program of Northeastern University
There are no eligibility restrictions based on nationality. All highly qualified applicants are encouraged to apply.
Differential stoichiometry among core ribosomal proteins, Cell Reports, vol. 13, Issue 5, p865–873
Slavov N., Budnik B., Schwab D., Airoldi E., van Oudenaarden A. (2014)
Constant Growth Rate Can Be Supported by Decreasing Energy Flux and Increasing Aerobic Glycolysis
Cell Reports, vol. 7, Issue 3, p705–714
Preiss, Thomas (2016)
All Ribosomes Are Created Equal. Really?
Trends in biochemical sciences, vol. 41, Issue 2, p121-123
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